Process for affecting the setting and working time of bioresorbable calcium phosphate cements

ABSTRACT

A fast-setting, bioresorbable calcium phosphate cement is prepared by a process which can be carried out with a heat treatment up to 1000° C. on a mixture of a wetting solution and a calcium phosphate powder having a Ca to P molar ratio of 0.5-2.5. The wetting solution suitable for use in the process of the present invention includes water, an organic solvent, an acidic and basic solution. A setting solution for mixing with the heated powder to form the fast-setting, bioresorbable calcium phosphate cement may be water, an acidic or basic solution according to the process of the present invention.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This is a continuation of and claims the benefit of priority under 35 USC § 120 to U.S. patent application Ser. No. 11/137,112, filed May 25, 2005, which is a continuation of U.S. patent application Ser. No. 10/944,278, filed Sep. 17, 2004, which is a continuation of U.S. patent application Ser. No. 10/328,019, filed Dec. 26, 2002, now U.S. Pat. No. 6,840,995, which is a continuation-in-part application of U.S. patent application Ser. No. 09/615,384, filed Jul. 13, 2000, now abandoned, which is a continuation-in-part application of U.S. patent application Ser. No. 09/351,912, filed Jul. 14, 1999, now U.S. Pat. No. 6,379,453B1. The above-listed applications are commonly assigned with the present invention and the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for producing fast-setting, bioresorbable calcium phosphate cements (CPC), and in particular, to a process including a pre-heat treatment step to generate whiskers or fine crystals on surfaces of the CPC particles.

2. Description of the Related Art

U.S. Pat. No. 6,379,453B1 which is commonly assigned with the present invention discloses a process for producing a fast-setting, bioresorbable calcium phosphate cement comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca₄(PO₄)₂O, CaHPO₄.2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂P₂O, wherein the molar ratio of Ca to P in the mixture is roughly between 1 and 2; mixing the powder mixture in a phosphate-containing solution to obtain a powder/solution mixture having a concentration of less than 4 g powder mixture per ml solution; immediately heating the powder/solution mixture to a temperature of roughly 50° C. to 350° C. to obtain a powder containing uniformly distributed submicron-sized apatite crystals; and mixing the apatite crystal-containing powder in a phosphate ion-containing solution to obtain a fast-setting, bioresorbable calcium phosphate cement.

SUMMARY OF THE INVENTION

An extensive study on the preparation of the fast-setting, bioresorbable calcium phosphate cement disclosed in U.S. Pat. No. 6,379,453B1 has been conducted by the same inventors and their co-workers, and found that the fast-setting, bioresorbable calcium phosphate cement can be prepared under various conditions. Therefore an object of the invention is to provide a more comprehensive process for producing a fast-setting, bioresorbable calcium phosphate cement.

The invention accomplishes the above object by providing a process which can be carried out with a heat treatment up to 1000° C. on a mixture of a wetting solution and a calcium phosphate powder having a Ca to P molar ratio of 0.5-2.5. The wetting solution suitable for use in the process of the present invention includes water, an organic solvent, an acidic and basic solution, not limited to the phosphate-containing solution. A setting solution for mixing with the heated powder to form the fast-setting, bioresorbable calcium phosphate cement may be an acidic solution, a basic solution or substantially pure water according to the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The preferred embodiments of the present invention include (but not limited to) the following:

1) A process for producing a fast-setting, bioresorbable calcium phosphate cement, comprising the following steps:

(a) obtaining a calcium phosphate powder comprising at least one calcium phosphate selected from the group consisting of Ca₄(PO₄)₂O, CaHPO₄.2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂H₂P₂O₈, wherein the molar ratio of Ca to P in said calcium phosphate powder is between about 0.5 and 2.5;

(b) mixing said calcium phosphate powder obtained from step (a) with a wetting solution to obtain a powder/solution mixture in a ratio of less than about 10 g powder per ml solution;

(c) heating the powder/solution mixture resulting from step (b) to a temperature up to about 1000° C. and

(d) mixing the resulting dried powder from step (c) in a setting solution to obtain the fast-setting, bioresorbable calcium phosphate cement.

2) The process as set forth in item 1), wherein said Ca/P molar ratio in step (a) is between 1.0 and 2.0.

3) The process as set forth in item 2), wherein in step (d) the resulting dried powder from step (c) together with at least one additive selected from the group of sodium phosphate (Na₃PO₄), disodium hydrogen phosphate (Na₂HPO₄), sodium dihydrogen phosphate (NaH₂PO₄), disodium hydrogen phosphate dodecahydrate (Na₂HPO₄.12H₂O), disodium hydrogen phosphate heptahydrate (Na₂HPO₄.7H₂O), sodium phosphate dodecahydrate (Na₃PO₄.12H₂O), orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄), Ca₄(PO₄)₂O, CaHPO₄.2H₂O, CaHP O₄, Ca₈H₂(PO₄)₆.5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, and Ca₂H₂P₂O₈, are mixed with the setting solution to obtain the fast-setting, bioresorbable calcium phosphate cement.

4) The process as set forth in item 3), wherein said wetting solution in step (b) is an acidic aqueous solution, a basic aqueous solution, an organic solvent, or substantially pure water.

5) The process as set forth in item 4), wherein the organic solvent is ethanol.

6) The process as set forth in item 1), wherein the mixing ratio in step (b) is less than about 5 g powder per ml solution.

7) The process as set forth in item 1), wherein the heating temperature in step (c) is up to about 500° C.

8) The process as set forth in item 1), wherein the setting solution in step (d) is an acidic aqueous solution, a basic aqueous solution, or a substantially pure water.

9) The process as set forth in item 4) or 8), wherein the acidic aqueous solution is selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate (NH₄H₂PO₄), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.

10) The process as set forth in item 4) or 8), wherein the basic aqueous solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄.12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄.3H₂O), sodium bicarbonate (NaHCO₃), and their mixture.

11) The process as set forth in item 1) further comprising grinding the resulting dried powder from step (c) between step (c) and step (d).

12) The process as set forth in item 1), wherein the fast-setting, bioresorbable calcium phosphate cement obtained from step (d) has a viscosity so that it can be injected by a syringe.

The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.

EXAMPLE 1

To fabricate the CPC, the TTCP (Ca₄(PO₄)₂O) powder was prepared from the reaction of dicalcium pyrophosphate (Ca₂P₂O₇) (Sigma Chem. Co., St Louis, Mo., USA) and calcium carbonate (CaCO₃) (Katayama Chem. Co., Tokyo, Japan) using the method suggested by Brown and Epstein [Journal of Research of the National Bureau of Standards—A Physics and Chemistry 6 (1965) 69A 12], while the DCPA (CaHPO.sub.4) powder is a commercial product (Jassen Chemical Co., Japan).

5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml of a wetting solution of a phosphoric acid aqueous solution having a pH of 1.96 were mixed, and stirred for one minute. The resulting mixture was placed into an oven at 50° C. for 15 minutes, and the resulting dried mixture was mechanically ground for 20 minutes to fine particles after being removed from the oven. 1 g of the fine particles and 0.4 ml of phosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a paste, which was tested every 30 seconds to determine the working time and the setting time. The setting time is the time required when a 1 mm diameter pin with a load of ¼ pounds can be inserted only 1 mm deep into the surface of the paste. The working time is the time after which the paste is too viscous to be stirred. The working time of the paste of this example is 6.5 minutes and the setting time thereof is 11.5 minutes.

The paste was placed in a relatively large amount of deionized water immediately following the formation thereof, and it was observed that the paste was non-dispersive in deionized water.

EXAMPLES 2-5

The procedures of Example 1 were repeated except that the heat treatment at 50° C. for 15 minutes was changed according to the conditions listed in Table 1. The performance is also listed in Table 1.

TABLE 1 Controlling Setting/working time treatment (min) Dispersive in water Ex. 1 Heating, 50° C. 11.5/6.5 No Ex. 2 Heating, 100° C. 13.5/8.0 No Ex. 3 Heating, 150° C.  8.5/8.0 No Ex. 4 Heating, 500° C.  2.5/1.5 No Ex. 5 Heating, 1000° C.  35/31 No

EXAMPLES 6-10

The procedures of Example 1 were repeated by using the calcium phosphate powders and the wetting solutions listed in Table 2. The performance is also listed in Table 2.

TABLE 2 Calcium Setting/ phosphate Wetting working time Dispersive powder solution (min) in water Ex. 6 TCP Phosphoric 10/6.5 No acid Ex. 7 TCP Ethanol 12.5/8.5   No Ex. 8 TTCP + DCPA Phosphoric 11/8   No acid Ex. 9 TTCP + Phosphoric — No DCPA + TCP acid Ex. 10 DCPA + TCP Phosphoric 29/24  No acid

EXAMPLES 11-22

The procedures of Example 1 were repeated by using the wetting solutions having different pH values listed in Table 3. The performance is also listed in Table 3.

TABLE 3 Dispersive Wetting solution pH in water Ex. 11 Phosphoric acid 0.56 No Ex. 12 Phosphoric acid 1.03 No Ex. 13 Phosphoric acid 1.17 No Ex. 14 Phosphoric acid 1.22 No Ex. 15 Phosphoric acid 1.32 No Ex. 16 Phosphoric acid 2.0 No Ex. 17 Acetic acid + 7.0 No sodium carbonate Ex. 18 Sodium hydroxide 9.5 No Ex. 19 Sodium hydroxide 12.55 No Ex. 20 Acetic acid 1.96 No Ex. 21 Ethanol — No Ex. 22 Deionized water 7.0 No

In the following examples, different setting solutions were used to verify the effect of the setting solution on the non-dispersive property of the calcium phosphate cement.

EXAMPLES 23-30

5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml of a wetting solution of 25 mM phosphoric acid aqueous solution were mixed, and stirred for one minute. The resulting mixture was placed into an oven at 50° C. for 15 minutes, and the resulting dried mixture was mechanically ground for 20 minutes to fine particles after being removed from the oven. 1 g of the fine particles and 0.4 ml of the setting solutions listed in Table 4 were mixed to form a past, which was tested every 30 seconds to determine the working time and the setting time as defined in Example 1. The results are shown in Table 4.

EXAMPLES 31-33

The procedures of Example 23 were repeated except that an additive as shown in Table 4 was added to the mixed powder of DCPA and TTCP in a weight ratio of 1:10 after the mixed powder was removed from the oven, and the setting solution used in these examples was deionized water. The results are shown in Table 4.

EXAMPLES 34-45

To 5 g TTCP powder which was used as synthesized 10 ml of 1M phosphoric acid aqueous solution was poured, and the mixture was filtered immediately. The filtered cake was placed into an oven at 150° C. for 10 minutes, and the resulting dried mixture was mechanically ground for 5 hours to fine particles. The resulting heat-treated TTCP fine particles and the TTCP powder as synthesized (without heat treatment) were mixed in a weight ratio of 1:1.1 g of the mixed TTCP powder and 0.4 ml of the setting solutions listed in Table 4 were mixed to form a paste, which was tested every 30 seconds to determine the working time and the setting time as defined in Example 1. The results are shown in Table 4.

TABLE 4 Setting Setting Dispersive time/working Powder solution pH in water time (min) Ex. 23 TTCP + DCPA 25 mM H₃PO₄ 1.96 No Ex. 24 TTCP + DCPA Acetic acid No Ex. 25 TTCP + DCPA HNO₃ No Ex. 26 TTCP + DCPA HCl No Ex. 27 TTCP + DCPA (NH4)HPO₄ 7.96 No 13.0/8.0  Ex. 28 TTCP + DCPA K₂HPO₄ 8.76 No 31.0/23.5 Ex. 29 TTCP + DCPA NaOH 13.57 No 28.0/19.0 Ex. 30 TTCP + DCPA Deionized 7.0 No water Ex. 31 TTCP + DCPA + Deionized 7.0 No phosphoric acid water Ex. 32 TTCP + DCPA + Deionized 7.0 No 20.5/16.5 NaH₂PO₄.2H₂O water Ex. 33 TTCP + DCPA + Deionized 7.0 No 11.0/7.0  Na₂HPO₄.2H₂O water Ex. 34 TTCP Deionized 7.0 No 35.0/31.0 water Ex. 35 TTCP 3M H₃PO₄ −0.7 No 17.5/16.0 Ex. 36 TTCP HCl −1.53 No Ex. 37 TTCP HCl −0.83 No 22.5/17.5 Ex. 38 TTCP HNO₃ −1.53 No Ex. 39 TTCP HNO₃ −0.83 No   33/28.5 Ex. 40 TTCP HNO₃ 0 No 27.5/22.0 Ex. 41 TTCP HNO₃ 2 No 20.5/16.0 Ex. 42 TTCP K₂HPO₄ 8.76 No 9.0/7.5 Ex. 43 TTCP (NH₄)₂HPO₄ 7.96 No 8.5/6.5 Ex. 44 TTCP CH₃COOH No 4.5/3.5 Ex. 45 TTCP NaOH 13.57 No 52/30

Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims. Many modifications and variations are possible in light of the above disclosure. 

1. A method of making a calcium phosphate cement (CPC) paste having either a desired setting time or a desired working time, the method comprising: contacting a calcium phosphate powder comprising one or more calcium phosphates with a wetting solution to form a mixture, the calcium phosphate powder having a Ca/P molar ratio in the range of 0.5-2.5; drying the mixture by heating the mixture at a temperature of up to about 1000° C.; forming calcium phosphate cement particles from the heated mixture; and contacting the calcium phosphate cement particles with a sufficient volume of a setting solution to form an injectable paste; wherein one or more of the calcium phosphates, the wetting solution, the setting solution, and the temperature that the mixture is heated to is selected such that the injectable paste has either a setting time in the range of 2.5 min to 35 min or a working time in the range of 1.5 min to 31 min.
 2. The method of claim 1, wherein the calcium phosphates, the setting solution and the temperature that the mixture are heated to is selected such that the injectable paste has a setting time in the range of 10 min to 29 min.
 3. The method of claim 1, wherein the temperature that the mixture is heated to is less than about 500° C.
 4. The method of claim 1, wherein the calcium phosphates, the setting solution and the temperature that the mixture is heated to are selected such that the injectable paste has a working time in the range of 2.5 min to 30 min.
 5. The method of claim 1, wherein the CPC powder comprises one or more of Ca₄(PO₄)₂O, CaHPO₄•2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆•5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂H₂P₂O₈.
 6. The method of claim 1, wherein the CPC powder comprises a mixture of Ca₄(PO₄)₂O and CaHPO₄.
 7. The method of claim 1, wherein the wetting solution is an acidic solution, basic solution, a phosphate-containing solution, an organic solvent, or water.
 8. The method of claim 1, wherein the organic solvent is ethanol.
 9. The method of claim 1, wherein the wetting solution is an acidic aqueous solution comprising one or more of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate (NH₄H₂PO₄), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, and oxalic acid.
 10. The method of claim 1, wherein the wetting solution is a basic aqueous solution comprising one or more of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄•12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄.3H₂O), sodium bicarbonate (NaHCO₃).
 11. The method of claim 1, wherein the ratio of CPC powder to wetting solution in the mixture is less than 10 mg/ml.
 12. The method of claim 1, wherein the calcium phosphate powder further comprises at least one additive selected from the group of sodium phosphate (Na₃PO₄), disodium hydrogen phosphate (Na₂HPO₄), sodium dihydrogen phosphate (NaH₂PO₄), disodium hydrogen phosphate dodecahydrate (Na₂HPO₄•12H₂O), disodium hydrogen phosphate heptahydrate (Na₂HPO₄•7H₂O), sodium phosphate dodecahydrate (Na₃PO₄•12H₂O), orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄), Ca₄(PO₄)₂O, CaHPO₄•2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆•5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, and Ca₂H₂P₂O₈.
 13. The method of claim 1, wherein the Ca/P molar ratio of the calcium phosphate powder is in the range of about 0.5 to 2.5.
 14. The method of claim 1, wherein the Ca/P molar ratio of the calcium phosphate powder is in the range of about 1.0 to about 2.0.
 15. The method of claim 1, wherein the temperature that the mixture is heated to is selected such that the injectable paste has a working time in the range of 6.5 minutes to 24 min.
 16. The method of claim 1, wherein the setting solution is an acidic aqueous solution, a basic aqueous solution, or substantially pure water.
 17. The method of claim 1, wherein the setting solution is an acidic aqueous solution comprising one or more of nitric acid (HNO3), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate (NH₄H₂PO₄ malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, and oxalic acid.
 18. The method of claim 1, wherein the setting solution is a basic aqueous solution comprising one or more of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄•12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄•3H₂O), and sodium bicarbonate (NaHCO₃). 